The pathogenic roles of the complement system in many human diseases have become increasingly understood, in large part through the results of informative clinical trials. In addition, based on biomarker studies in patients and results of murine models, there are an increasing number of indications under consideration for the use of therapeutics targeting different components of the pathway. Here, lessons learned from several of these studies are reviewed, with an emphasis on diseases of clinical and research interest to rheumatologists. Publications focused on the complement-related pathogenesis and clinical trials of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and rheumatoid arthritis (RA), in addition to studies relevant to other diseases, are summarised. Following translational studies demonstrating activation in affected tissues and blood from patients, the potential pathogenic roles of complement in AAV and RA were studied in murine models. These studies suggested in both diseases that complement alternative pathway generation of C5a is a primary driver of target organ damage. In AAV, clinical trials using a novel small molecular oral C5a anaphylatoxin receptor (C5aR1) antagonist revealed a substantial corticosteroid-sparing effect and initial evidence of clinical benefit. With regard to RA, although there is strong support through biomarker and murine model studies, intervention with C5 and C5aR1 inhibitors revealed only modest benefit, and additional work is necessary to determine if different targets or timing of intervention is necessary. Beyond AAV and RA, a substantial number of additional diseases cared for by rheumatologists exhibit evidence of complement activation in a potentially pathogenic manner. Inappropriate activation of the complement pathway mediates tissue inflammation and damage in many human diseases, including key ones cared for by rheumatologists.
This study aimed to clarify the latest epidemiologic trends, economic costs, and key drivers of musculoskeletal disorders (MSDs) in high-income regions, where the disease burden has increased despite high overall healthcare spending. Utilising data from the Global Burden of Disease 2023 database, we analysed the trends in incidence, prevalence, and years lived with disability (YLDs) for MSD across 36 high-income countries from 1990 to 2023. Bayesian meta-regression models were employed to quantify the burden attributable to major risk factors. A cross-national transfer model was used to estimate the direct healthcare economic costs associated with MSD in 2023. Spearman correlation analysis was applied to explore the relationship between the Sociodemographic Index (SDI) and disease burden, and trends in disease burden were forecasted for the period 2024 to 2050. Between 1990 and 2023, the total number of incident cases, prevalent cases, and YLDs for MSD in high-income regions increased by 36.75%, 54.28%, and 49.36%, respectively. Although the age-standardised incidence rate decreased by 4.07%, the standardised prevalence and YLD rates increased by 5.04% and 3.98%, respectively, indicating a continuously growing absolute disease burden. Low back pain and osteoarthritis accounted for the largest proportion of the disease burden. For all MSD subtypes except gout, the burden was higher in females than in males. In 2023, the direct medical costs associated with MSD reached as high as $327.68 billion, with the United States accounting for >45% of this amount. Regarding risk factors, the proportion of YLDs attributable to high body mass index increased from 8.3% in 1990 to 10.7% in 2023. The contribution of occupational ergonomic factors remained stable at approximately 7.7%, whereas the smoking-related burden decreased by 30%. Correlation analysis revealed no significant association between the SDI and the age-standardised burden rates of MSD. The burden of MSD in high-income regions continues to intensify, driven primarily by ageing, obesity, and occupational factors, and has not been alleviated by economic development. Future prevention and control efforts should focus on weight management and occupational ergonomic interventions to curb the growth of the disease and mitigate the substantial economic pressure.
This study aimed to analyse structural and functional mitochondrial alterations, the release of mitochondrial DNA (mtDNA), and the activation of inflammatory signalling pathways that can be reversed by tofacitinib in the salivary glands (SG) of patients with Sjögren's disease (SjD). SG from patients with SjD and controls, as well as from mice with SjD treated with or without tofacitinib, were analysed. We determined the mitochondrial ultrastructure, the presence of mtDNA in the cytosol, and the levels and localisation of pattern recognition receptors (PRRs) that recognise mtDNA. The adenosine triphosphate (ATP) levels and oxygen consumption rate (OCR) were measured to evaluate mitochondrial respiration in frozen SG. We also evaluated the OCR in human submandibular gland cells incubated with interferon-gamma (IFN-γ), tofacitinib, or both. Increased mtDNA release into the cytosol was observed in SG epithelial cells of patients with SjD. This change was linked with increased PRR activation (cyclic GMP-AMP synthase, Z-DNA-binding protein 1, and nucleotide-binding oligomerisation domain-like receptor protein 3) and decreased mitochondrial transcription factor A (TFAM). Similar mitochondrial ultrastructural alterations and increased PRR activation were observed in the SG of the SjD mouse model. These changes were reversed by tofacitinib. Interestingly, increased activity of electron transport chain complexes was observed in SG of patients with SjD, which could be modulated by IFN-γ, as observed in vitro. We also found that tofacitinib stabilised mitochondrial function at basal conditions in vitro, counteracting the mitochondrial adaptations induced by IFN-γ. Taken together, these results suggest that mitochondrial alterations are linked with inflammation and support the potential use of tofacitinib in patients with SjD.
The integration of artificial intelligence (AI) into research and publishing poses ethical challenges. Global editorial associations, including the International Committee of Medical Journal Editors (ICMJE), have updated their recommendations to safeguard transparency and accountability for AI use. The extent to which these recommendations have been enforced in specialist journals remains unknown. The aim of our study was to analyze the extent to which indexed rheumatology journals have adopted AI-related editorial policies, the scope of these policies, and their alignment with ICMJE recommendations. A total of 58 impact-factor rheumatology journals were analyzed in view of their AI-related editorial policies. Author instructions, ethics statements, and publisher guidelines were overviewed for (1) AI-related instructions; (2) alignment with ICMJE recommendations; (3) provisions regulating AI use by authors, peer reviewers, and editors; and (4) regulations concerning generative text, images, data, and analytical outputs. Of the 58 journals, 45 (77.6%) presented explicit AI editorial policies, while 13 (22.4%) lacked any AI-related guidance. The majority of journals (98.2%) endorsed ICMJE points on AI. High-impact journals-Nature Reviews Rheumatology, The Lancet Rheumatology, and Annals of the Rheumatic Diseases-demonstrated the most stringent governance, prohibiting AI use for analytical and creative roles, mandating detailed disclosure of AI tools and prompts, and banning AI use for peer review and editorial decision-making. The guidance on AI use by peer reviewers and editors was present in 45 journals (77.6%). Permissive uses of AI were largely confined to language editing under human supervision. Generative or substantive uses-such as producing figures, conceptual contents, or data-were broadly restricted. Indexed rheumatology journals demonstrate variable editorial policies of enforcing AI guidance. While the adoption of AI-related policies is mostly improving, a marked heterogeneity still exists, particularly between top-tier and lower-tier journals. Upgrades of editorial policies are warranted to safeguard the integrity and transparency of rheumatology sources.
The primary objective of this randomised, active-controlled, international, multicentre, phase IV clinical trial was to demonstrate noninferiority of the response of ultrasound-assessed synovitis to baricitinib treatment, alone and in combination with methotrexate (MTX), compared with etanercept with MTX in rheumatoid arthritis (RA). Adult patients with active RA and inadequate response to MTX were randomised into 3 parallel treatment groups: baricitinib monotherapy, baricitinib plus MTX, and etanercept plus MTX. The patients underwent clinical, ultrasound, and laboratory assessments at baseline, 4, 12, and 24 weeks. Ultrasound synovitis was scored 0 to 3 in B-mode, Doppler mode, and a combination of both modes. The primary endpoint was the change in the Global European Alliance of Associations for Rheumatology-Outcome Measures in Rheumatology Synovitis Score (GLOESS) for bilateral wrist and metacarpophalangeal joints at week 12. Noninferiority was stated if the changes in the baricitinib groups were above the lower limit of the noninferiority range, defined as 80% of changes observed in the etanercept plus MTX group. Changes in serum concentrations of different mediators were analysed at 24 weeks. One hundred fifty patients (109 women and 41 men) were randomised. All clinical and ultrasound variables showed significant improvement starting from week 4 across the 3 treatment arms (P < .050). Noninferiority of baricitinib (monotherapy and plus MTX) was confirmed against etanercept with MTX for GLOESS at week 12 (P < .050). Changes in metalloprotease-3 concentration significantly correlated with changes in all ultrasound scores. The response of ultrasound-assessed synovitis to baricitinib, alone or in combination with MTX, was noninferior to that of etanercept with MTX.
Autoantibodies directed against Telomerase RNA Ro y-RNAs and Vault RNAs Domain Family Member 2 (TROVE2)/Ro60 and Tripartite Motif 21 (TRIM21)/Ro52 are historically related to distinct SSA/Ro autoantigens. However, despite advances facilitating separate testing, these autoantibodies remain frequently confused resulting in a lack of clarity and precision in the literature. We conducted a systematic literature review to inform a Delphi process to achieve consensus on a clearer, harmonised nomenclature. The systematic review included primary publications in systemic lupus erythematosus (SLE) and Sjögren disease (SjD) published between January 1, 2000 and May 26, 2025 that mentioned testing for anti-TROVE2/Ro60 and/or anti-TRIM21/Ro52 autoantibodies. This analysis contributed to a Delphi consensus exercise proposing preferred nomenclature by a group of 17 international expert physicians and laboratorians. Eight hundred ninety-one publications were included (301 SLE, 493 SjD, and 97 mixed SLE/SjD). Only 20.9% of studies tested and reported the autoantibodies separately; 75.0% did neither; and 4.2% tested but did not report them separately. There was considerable nomenclatural heterogeneity with 16 different terms used for anti-TROVE2/Ro60 and 11 terms for anti-TRIM21/Ro52 autoantibodies. After 2 rounds of voting, the Delphi panel reached a unanimous consensus on the terms anti-TROVE2/Ro60 and anti-TRIM21/Ro52 autoantibodies. The distinction of anti-TROVE2/Ro60 and anti-TRIM21/Ro52 autoantibodies was frequently unclear and imprecise throughout the literature. Their clinical associations also lacked clarity and precision. To clarify and strengthen the understanding of the clinical associations of these 2 important autoantibodies, the terms anti-TROVE2/Ro60 and anti-TRIM21/Ro52 are recommended for future studies and publications.
Sjögren's syndrome (SS) is a chronic, systemic inflammatory disorder primarily characterized by dry eyes and dry mouth, often involving multiple organ systems. The disease's heterogeneous clinical presentation and the absence of non-invasive, specific biomarkers complicate its diagnosis and prognostic assessment. Literature was sourced from the Web of Science Core Collection, and a bibliometric network was constructed using VOSviewer, CiteSpace, and Bibliometrix. This analysis covered countries/regions, institutions, journals, authors, citations, and keywords, offering an overview of SS biomarker research and identifying future directions. A total of 1118 articles on SS biomarkers were analyzed. Publication trends fluctuated over the years, with China and the United States leading in volume and citation frequency. The Assistance Publique-Hôpitaux de Paris was the most prolific institution. Among researchers, Xavier Mariette dominated the field, with leading positions in volume of publications, h-index, and total citations. Annals of the Rheumatic Diseases emerged as the most influential journal. Over the past two decades, research has expanded significantly, with emerging themes including "DNA methylation," "genes," "interstitial lung disease," and "data-driven," indicating future focus areas such as epigenetics, severe complication biomarkers, and multi-omics studies. This bibliometric analysis provides a comprehensive view of SS biomarker research, highlighting recent trends and future research directions, offering valuable insights for ongoing studies.
Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is the leading cause of mortality in systemic sclerosis (SSc), yet its genetic architecture remains incompletely understood. Therefore, given the key role of the major histocompatibility complex (MHC) in SSc, we aimed to perform a comprehensive MHC-wide association study in the largest SSc-ILD cohort to date. We analysed 2412 patients with SSc-ILD⁺, 3550 patients with SSc-ILD⁻, and 15,076 controls of European ancestry from 10 international cohorts. After quality control, the MHC region was imputed, and inverse variance weighted meta-analysis was performed. Subsequently, conditional stepwise analyses, adjustment for antitopoisomerase autoantibody (ATA) status, and functional annotation of significant single-nucleotide polymorphisms were performed. Finally, we constructed a composite score combining genetic, clinical, and demographic variables to predict SSc-ILD. After conditional analysis, we detected 12 significant associations within class I and class II human leukocyte antigen (HLA) genes. ATA adjustment reduced the significance of class II HLA variants, whereas class I HLA variants remained unaffected. Finally, the built composite score had an area under the curve of 0.754, significantly outperforming the models including any of the variables alone. In this study, we identify genetic mechanisms underlying SSc-ILD that support the potential implication of CD8+ T cells and ATAs in its pathogenesis. Moreover, we also demonstrate the enhanced efficacy of integrating genetic information into predictive models to detect patients at high risk of SSc-ILD. These findings provide new insights into disease pathogenesis and suggest potential biomarkers and therapeutic targets for improved patient management.
This systematic literature review (SLR) updated evidence on the efficacy of disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) to inform the 2025 update of the European Alliance of Associations for Rheumatology (EULAR) management recommendations for rheumatoid arthritis (RA). Medline (PubMed), Embase (OVID), Cochrane Central Register of Controlled Trials, and Web of Science were searched for randomised controlled trials (RCTs) of conventional-synthetic, biological, and targeted-synthetic DMARDs (csDMARDs, bDMARDs, tsDMARDs), as well as GCs and biosimilars, published from 14 January 2022 to 22 January 2025. Additional searches on DMARDs, GCs, and antifibrotics for RA-associated interstitial lung disease (RA ILD), and on DMARDs and GCs for preventing RA in at-risk individuals, were conducted from database inception to 22 January 2025. A total of 12,567 references were identified; 390 full-texts were reviewed, and 72 studies were included. Phase 3-4 RCTs evaluated csDMARDs (hydroxychloroquine, iguratimod, leflunomide, and methotrexate), bDMARDs (abatacept, otilimab, and ozoralizumab), and tsDMARDs (ivarmacitinib, peficitinib, and tofacitinib). Twelve novel compounds were assessed in phase 2 RCTs, and 3 articles investigated GCs. Strategic trials compared conventional therapies with bDMARD- or tsDMARD-based strategies and explored precision-medicine approaches such as synovial biopsy-guided treatment and therapeutic drug monitoring. Additional evidence addressed DMARD tapering. Two RCTs assessed antifibrotics (nintedanib and pirfenidone) for RA ILD, and 7 studies evaluated DMARDs for RA prevention in at-risk populations. This SLR, together with the safety review, informed the 2025 update of the EULAR RA management recommendations. Although few phase 3 trials on novel agents were available, strategic and head-to-head studies provided important insights that enabled further refinement of the established treatment algorithm.
Lupus nephritis (LN) is a common, potentially fatal manifestation of systemic lupus erythematosus. We aimed to gain new insights into the immune responses underlying LN and their relation to the histologic heterogeneity observed in this disease, focusing on myeloid cells. We used single-cell RNA-sequencing (scRNA-seq) data of dissociated kidney samples from 156 patients with LN and 30 healthy individuals. We applied spatial transcriptomics (ST), utilising a gene panel designed to capture all myeloid subsets identified in the scRNA-seq data, to profile kidney samples acquired from 6 patients with LN and 2 controls. We generated a catalogue of the myeloid subsets found in LN kidneys. Our analyses indicated that an increase in irreversible tissue damage, as measured by the National Institutes of Health chronicity index (CI), is associated with a gradual switch of the local immune response from one dominated by monocytes and macrophages to one featuring expanded CD4 T, GZMK+ CD8 T, B, and dendritic cells, with a parallel decrease in the interferon response. In proliferative/mixed LN only, the degree of active inflammation correlates with the expansion of disease-specific macrophage (DMac) subsets, which later contract as the CI increases. Trajectory analysis of the scRNA-seq data suggested that DMacs arise from both infiltrating monocytes and tissue-resident macrophages; this was supported by the ST data, as well as cell cultures. DMacs are implied to interact with parietal epithelial cells, promoting the development of glomerulosclerosis. We suggest a detailed picture of the changes in the kidney immune mechanisms in LN as this disease progresses.
Rheumatic and musculoskeletal diseases (RMDs) present a substantial yet often underrecognised public health challenge. This viewpoint article highlights significant sex- and gender-based disparities, where women are disproportionately affected by prevalence, diagnosis, treatment, and occupational risk factors. Many prevalent RMDs, including osteoarthritis, rheumatoid arthritis, systemic lupus erythematosus, and fibromyalgia, exhibit a higher prevalence and greater burden in women. Women frequently experience prolonged diagnostic delays, receive incorrect initial diagnoses, and face unequal access to effective treatments, often leading to worse outcomes. Occupational factors, such as organisational strain and repetitive tasks, also render women more susceptible to RMDs. These inequities are compounded by biases in medical education, research, and clinical practice, where women's symptoms are often dismissed or normalised. The impact extends to reproductive health, mental well-being, and socio-economic stability for women with RMDs. Addressing these pervasive disparities is paramount for achieving health equity and improving overall public health. We advocate for the urgent inclusion of RMDs within the growing Women's Health agenda, particularly at the European Union level, to drive targeted research, implement gender-sensitive diagnostic and treatment strategies, and revise medical education. Collective action is essential to ensure RMDs and their disproportionate impact on women gain the visibility and policy prioritisation they demand.
Osteoarthritis represents a prevalent degenerative joint disorder. Obesity influences its onset and progression through multifactorial mechanisms encompassing biomechanical stress and systemic inflammation. This study aims to delineate the current research landscape and identify emerging thematic frontiers. Literature pertaining to obesity and osteoarthritis was retrieved from the Web of Science Core Collection database, spanning publications from January 2006 to November 2025. Bibliometric analyses were conducted using CiteSpace, VOSviewer, and the Bibliometrix R package. A total of 4956 publications were analyzed, revealing a consistent linear growth trajectory. The United States emerged as the predominant contributor, yielding the highest publication output (n = 1643) and citation impact (total citations = 103,451). The University of Sydney constitutes a pivotal institution within this field. Journals including Osteoarthritis and Cartilage and Annals of the Rheumatic Diseases served as principal platforms for high-impact scholarship. David J. Hunter was identified as the most influential author. Keyword clustering delineated inflammation, exercise, prevalence, total knee arthroplasty, body composition, and hyaluronic acid as core research domains, whereas contemporary frontiers converge on adipokines, apoptosis, and oxidative stress. Research at the obesity-osteoarthritis nexus has attracted considerable attention in recent years. This bibliometric analysis elucidates the interrelationship between these conditions while clarifying prevailing research priorities and developmental trajectories, thereby informing future investigative directions.
Tofacitinib is a Janus kinase inhibitor studied in different categories of juvenile idiopathic arthritis (JIA). This post hoc analysis evaluated the impact of tofacitinib on the growth of patients with JIA and on biomarkers of growth hormone (GH) function and bone metabolism. The analysis included 225 patients, primarily with polyarticular-course JIA, receiving long-term tofacitinib (median [IQR] follow-up 3.6 [1.9-4.6] years). Height velocities (cm/y) and height Z-scores (based on age- and sex-matched reference data) were calculated. Biomarkers were measured in serum from 137 patients with JIA completing 18 weeks of open-label treatment with tofacitinib. This population of patients with JIA had a baseline height distribution similar to the general population. During treatment with tofacitinib, patients experienced height velocities that appeared greater (patients ≤12 years) or as expected (patients >12 years) relative to the reference for their ages. Height Z-scores were largely stable during treatment with tofacitinib. In patients in puberty and a height Z-score less than --1.0 at baseline, an increase in height Z-score (P < .05) was detected after 24 months of treatment. Tofacitinib treatment did not impact levels of insulin-like growth factor (IGF)-1, IGF binding protein 3 and osteocalcin in the overall population, but in patients aged 6 to 12 years, IGF-1 levels increased with tofacitinib from baseline to 18 weeks. This post hoc analysis of patients with JIA indicated normal or higher than expected growth velocity during long-term treatment, with tofacitinib with catch-up growth during puberty and, overall, no concerning changes in biomarkers of GH signalling.
This study aimed to evaluate the efficacy and safety of intravenous (IV) efgartigimod in adults with Sjögren's disease (SjD). We conducted a randomised, double-blinded, placebo-controlled, phase 2, proof-of-concept multicentre study (hereafter referred to as RHO). Participants were randomised 2:1 to receive efgartigimod IV 10 mg/kg or placebo once weekly for 24 weeks. The primary outcome was the proportion of Composite of Relevant Endpoints for Sjögren's Syndrome (CRESS) responders on ≥3 of 5 items (systemic disease activity, patient-reported symptoms, tear and salivary gland function, and serology) at week 24. Secondary outcomes included the proportion with candidate Sjögren's Tool for Assessing Response (cSTAR) score ≥5 at week 24 and safety. No formal statistical hypothesis was tested. Thirty-four participants were randomised to efgartigimod (N = 23) or placebo (N = 11); 31 were included in the efficacy analysis. A numerically higher proportion of efgartigimod-treated participants responded to ≥3 items of CRESS at week 24 compared with placebo (45.5% vs 11.1%; treatment difference 34.4%). More specifically, efgartigimod scored higher on 4 of 5 CRESS items. Similarly, a numerically higher proportion of efgartigimod-treated participants scored ≥5 on the cSTAR at week 24 (efgartigimod, 54.5% vs placebo, 33.3%). Treatment-emergent adverse events were reported in 87.0% of efgartigimod-treated participants compared with 63.6% of those on placebo; all were grade 1 or 2 in severity. Data from the RHO study support proof of concept for efgartigimod in SjD. Further evaluation in a phase 3 study of efgartigimod in individuals with SjD is warranted. The trial was registered with ClinicalTrials.gov (NCT05817669).
To further understand the mechanism of action of deucravacitinib, an oral, selective tyrosine kinase 2 inhibitor, in patients with systemic lupus erythematosus (SLE) in the phase 2 PAISLEY SLE trial. RNA sequencing (RNA-seq) was performed on samples collected from baseline to week 32 in 363 patients and 56 healthy volunteers. Pharmacodynamics of differentially expressed genes (DEGs) were analysed with linear mixed-effects models using the statistical software package DREAM (differential expression for repeated measures). Single-sample gene set enrichment analysis (ssGSEA) was performed using MSigDB Hallmark and BloodGen3 gene modules. The xCell R package was used to digitally portray the blood cellular heterogeneity landscape. At baseline, 527 DEGs were identified in patients with SLE vs healthy volunteers (log2 fold change >1; adjusted P < .05). Deucravacitinib modulated up to 2529 genes and SLE-relevant gene sets, including interferon-regulated genes. ssGSEA showed that plasma cell gene sets decreased and myeloid cell gene sets reverted towards normal levels with deucravacitinib; xCell deconvolution revealed significant enrichment of dendritic cell populations with deucravacitinib vs placebo. At baseline, regulatory T-cell gene sets were increased in patients with SLE vs healthy volunteers and further increased with deucravacitinib. There were some variable, dose-dependent increases in naïve and memory B lymphocytes. Whole blood transcriptome profiling via RNA-seq revealed both expected and novel gene expression changes with deucravacitinib across multiple pathogenic pathways. These data demonstrate successful targeting of pathophysiologic immune mechanisms that should be validated in future studies and support continued evaluation of deucravacitinib in the phase 3 POETYK SLE trials.
A loss-of-function variant in deoxyribonuclease 1-like 3 (DNASE1L3), encoding Arg to Cys substitution at amino acid 206 (R206C), was previously identified as a heritable susceptibility factor for systemic sclerosis (SSc). We analysed mortality and pulmonary outcomes in patients with SSc with or without the DNASE1L3 R206C variant. Mortality, pulmonary hypertension (PH), and interstitial lung disease (ILD) were ascertained in the UTHealth Houston, Royal Free Hospital, and Johns Hopkins University cohorts. Mortality risk and precapillary PH time-to-event from SSc onset were estimated using Cox proportional hazards models. Meta-analyses were performed to generate overall risk estimates. In the mortality analysis (n = 2366 patients, 46.6% of whom were deceased), after adjustment for age of SSc onset and sex, DNASE1L3 R206C was associated with significantly greater mortality (hazard ratio [HR]: 1.16, 95% CI: 1.02-1.32). In the precapillary PH analysis (n = 1170 patients, 20.3% of whom had precapillary PH), after adjustment for age of SSc onset, sex, and the presence of ILD, DNASE1L3 R206C was associated with significantly greater precapillary PH risk (HR: 1.69, 95% CI: 1.31-2.19). The majority of patients with precapillary PH did not have ILD, indicating that they had WHO Group I, ie pulmonary arterial hypertension (PAH). We report a previously unknown impact of DNASE1L3 polymorphism on PAH susceptibility in SSc. The association between loss-of-function of an immunoregulatory gene (DNASE1L3) and PAH susceptibility supports further exploration of downstream sequelae of DNASE1L3 dysfunction in SSc pathogenesis and the mechanisms underlying the well-recognised but poorly understood susceptibility of patients with SSc to PAH.
The objective of this study was to describe the musculoskeletal ultrasound features of asymptomatic hyperuricaemia using the Outcome Measures in Rheumatology (OMERACT) gout semiquantitative scoring system and examine relationships between ultrasound lesions. Participants with serum urate ≥0.48 mmol/L, no previous gout flares, and no subcutaneous tophi (n = 269) underwent a standardised ultrasound examination of bilateral patellar tendons, knee, first and second metatarsophalangeal joints (MTPs), and Achilles tendon. Double contour, tophus, and aggregates were scored according to the OMERACT gout ultrasound semiquantitative scoring system (0-3, with score >1 indicating a definite finding), together with erosion, synovial hypertrophy, and power Doppler activity in the scanned joints. In addition to elementary lesion sum scores, the sum of the semiquantitative double contour scores and tophus scores was calculated for each participant (semiquantitative double contour-tophus [SQDT] sum score, maximum 60). There were 38.7% of participants with at least 1 definite double contour and/or tophus on ultrasound. The median (IQR) SQDT sum score was 2 (0-4). Double contour scores contributed most to the SQDT sum score, followed by first MTP tophus scores. Double contour was associated with synovial hypertrophy at the first and second MTP, and tophus was associated with erosion, synovial hypertrophy, and power Doppler activity at the first MTP. Definite ultrasound features of gout can be identified in more than one-third of people with asymptomatic hyperuricemia. However, the amount of monosodium urate crystal deposition on ultrasound, assessed using the OMERACT gout ultrasound scoring system, is low. In asymptomatic hyperuricemia without clinical evidence of gout, ultrasound features of gout are associated with subclinical joint damage and inflammation.
Psoriatic arthritis (PsA) is a chronic immune-mediated inflammatory disease associated with psoriasis that can lead to progressive joint damage and impaired quality of life. Although biologic therapies targeting key inflammatory pathways have advanced rapidly, global research trends and hotspots in PsA treatment have not been systematically characterized. Publications on PsA treatment from 2014 to 2024 were retrieved from the Web of Science Core Collection. Bibliometric and visualization analyses were performed using CiteSpace and VOSviewer to evaluate publication characteristics, collaborative networks, and research trends, including keyword co-occurrence and citation burst analysis. A total of 2704 publications were included. The United States ranked first in both publication output and citations, with extensive international collaboration, particularly with European countries, while contributions from the Asia-Pacific region have increased in recent years. Research focus has shifted over time from tumor necrosis factor inhibitors and clinical validation studies to interleukin-17/23 inhibitors, Janus kinase inhibitors, and personalized treatment strategies. Annals of the Rheumatic Diseases was the most influential journal, and Mease PJ was the most productive author. Keyword and citation analyses indicated that precision medicine, novel therapeutic targets, and combination therapies are emerging research directions. Research on PsA treatment has evolved toward precision and targeted therapy. Future studies should emphasize biomarker-guided treatment and optimization of combination strategies to improve clinical outcomes.
Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and primary Sjögren's syndrome (pSS) frequently share overlapping clinical features, yet exhibit substantial intradisease heterogeneity in organ involvement and severity. This study aimed to define conserved molecular subtypes across these systemic autoimmune diseases (SADs) and delineate their transcriptional and epigenetic underpinnings. We profiled 262 treatment-naïve Chinese Han patients (RA: n = 109; SLE: n = 69; pSS: n = 84), predominantly female (83.2%), who were divided into discovery (n = 119) and validation (n = 143) cohorts. Bulk RNA sequencing defined molecular subtypes, which were correlated with clinical phenotypes. Chromatin accessibility and super-enhancer landscapes were mapped by Assay for Transposase-Accessible Chromatin with high-throughput sequencing and cleavage under targets and tagmentation, and single-cell RNA sequencing (scRNA-seq) was performed to delineate subtype-specific cellular compositions. Integrative analyses uncovered 2 robust and reproducible molecular subtypes, megakaryocyte-enriched and B-cell-enriched, which were consistent across all 3 SADs and both cohorts. The megakaryocyte-enriched subtype was associated with higher platelet counts, greater disease activity, and broader organ involvement. Epigenomic profiling identified distinct chromatin accessibility and regulatory architectures, with megakaryocyte-associated genes (eg, ZFP36L1 and RAD51B) linked to active superenhancers in the megakaryocyte-enriched subtype, and B-cell-associated genes (eg, MAF and PRDM1) in the B-cell-enriched subtype. scRNA-seq confirmed expansion of platelet-producing megakaryocytes and enhanced B-cell-activation signatures in their respective subtypes. Integrative multiomics profiling defines 2 conserved molecular subtypes across RA, SLE, and pSS with distinct cellular and regulatory programmes. This cross-disease taxonomy may inform precision stratification and the development of lineage-targeted therapies in SADs. Further multicentre validation and investigation of the epigenetic mechanisms underlying molecular subtypes are warranted.
The purpose of this paper is to investigate baseline predictors of unacceptable pain, overall and in patients with low inflammatory activity, as well as of pain over time, in patients with early rheumatoid arthritis (RA). We studied patients newly diagnosed with RA in Sweden in 2012-2020 (N = 10297), using data from several national registers. Pain was assessed by a Visual Analogue Scale (VAS; 0-100 mm). Unacceptable pain was defined as VAS pain > 40 mm, and low inflammation as C-reactive protein < 10 mg/L. Baseline predictors of unacceptable pain and unacceptable pain with low inflammation were evaluated using logistic regression analysis. Predictors of pain over time, from baseline to the 2-year follow-up, were investigated using linear mixed-effect models. Of the 3427 patients with data at 2 years, 1143 (33%) had unacceptable pain, and 808 (26%) had unacceptable pain with low inflammation. Female sex, worse patient-reported outcomes (PROs), low parameters of inflammation, and having many tender compared with swollen joints were baseline predictors of unacceptable pain and unacceptable pain with low inflammation at 1 and 2 years, and of more pain over time. Smoking, non-European origin, and having a psychiatric or pain-related comorbidity were also associated with more pain over time. Factors beyond inflammation contribute significantly to unacceptable pain at follow-up in RA. Physicians should be aware of the increased risk of unacceptable pain in patients with worse PROs and with discrepancies between the number of tender and swollen joints. Sex and cultural differences also need to be considered in future pain interventions in early RA.